DE3722007A1 - METHOD FOR PRODUCING BICYCLIC AMINOCARBONIC ACIDS, INTERMEDIATE PRODUCTS OF THIS METHOD AND THE USE THEREOF - Google Patents

METHOD FOR PRODUCING BICYCLIC AMINOCARBONIC ACIDS, INTERMEDIATE PRODUCTS OF THIS METHOD AND THE USE THEREOF

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DE3722007A1
DE3722007A1 DE19873722007 DE3722007A DE3722007A1 DE 3722007 A1 DE3722007 A1 DE 3722007A1 DE 19873722007 DE19873722007 DE 19873722007 DE 3722007 A DE3722007 A DE 3722007A DE 3722007 A1 DE3722007 A1 DE 3722007A1
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formula
compound
protecting group
compounds
alkyl
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German (de)
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Hansjoerg Dr Urbach
Rainer Dr Henning
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Hoechst AG
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Hoechst AG
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Priority to DE19873722007 priority Critical patent/DE3722007A1/en
Priority to FI883141A priority patent/FI92691C/en
Priority to CA000572358A priority patent/CA1332422C/en
Priority to HU883459A priority patent/HU203533B/en
Priority to JP63162750A priority patent/JP2564614B2/en
Priority to IE201988A priority patent/IE66150B1/en
Priority to US07/214,457 priority patent/US5011940A/en
Priority to NO882957A priority patent/NO173864C/en
Priority to KR1019880008172A priority patent/KR960012363B1/en
Priority to ZA884727A priority patent/ZA884727B/en
Priority to DK367488A priority patent/DK170373B1/en
Priority to AU18602/88A priority patent/AU617328B2/en
Priority to NZ225253A priority patent/NZ225253A/en
Priority to PT87904A priority patent/PT87904B/en
Priority to IL86943A priority patent/IL86943A0/en
Priority to ES88110612T priority patent/ES2065899T3/en
Priority to EP88110612A priority patent/EP0297620B1/en
Priority to AT88110612T priority patent/ATE114642T1/en
Priority to DE3852219T priority patent/DE3852219D1/en
Publication of DE3722007A1 publication Critical patent/DE3722007A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Peptides Or Proteins (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Compounds of the formula I <IMAGE> in which n is 1, 2 or 3, R denotes acyl and R<1> denotes alkyl, cycloalkyl, aralkyl or another carboxyl protecting group are prepared by free-radical cyclisation of compounds of the formula II <IMAGE> in which n, R and R<1> are as defined above and Hal denotes chlorine, bromine or iodine. Intermediates of this process and their use are also described.

Description

Acylderivate der Octahydroindol-2-carbonsäure, der Octahydrocyclopenta[b]pyrrol-2-carbonsäure bzw. der Decahydrocyclohepta[b]pyrrol-2-carbonsäure sind beispielsweise bekannt aus EP-A-79 022, EP-A-50 800, EP-A-84 164, EP-A-111 873, EP-A-37 231, US-Patent 43 50 704 oder US-Patent 45 87 258. Viele dieser Verbindungen zeigen eine bemerkenswerte biologische Aktivität. Sie hemmen beispielsweise hochwirksam das Angiotensin-Converting- Enzyme oder zeichnen sich durch eine nootrope Wirkung aus.Acyl derivatives of octahydroindole-2-carboxylic acid Octahydrocyclopenta [b] pyrrole-2-carboxylic acid or the Decahydrocyclohepta [b] pyrrole-2-carboxylic acid known for example from EP-A-79 022, EP-A-50 800, EP-A-84 164, EP-A-111 873, EP-A-37 231, US Patent 43 50 704 or US Patent 45 87 258. Many of these compounds show a remarkable biological activity. You inhibit for example, highly effective angiotensin converting Enzymes or are characterized by a nootropic effect.

Verbindungen der Formel ICompounds of formula I.

worin n=1-3, R Wasserstoff oder einen Acylrest und R¹ Wasserstoff, eine Estergruppe oder eine andere Carboxylschutzgruppe bedeuten, spielen eine Schlüsselrolle bei der Synthese der eingangs genannten Acylderivate.where n = 1-3, R is hydrogen or an acyl radical and R¹ is hydrogen, an ester group or another carboxyl protecting group, play a key role in the synthesis of the acyl derivatives mentioned at the beginning.

Oft ist es vorteilhaft, wenn das Kohlenstoffatom in Position 2 des bicyclischen Ringsystems dieser Wirkstoffe eine bestimmte absolute Konfiguration, vorzugsweise die S-Konfiguration aufweist. Man geht daher bei ihrer Synthese bevorzugt von Zwischenprodukten der Formel I aus, welche diese gewünschte Konfiguration am C-2 bereits aufweisen.It is often advantageous if the carbon atom is in Position 2 of the bicyclic ring system of these drugs a certain absolute configuration, preferably the S configuration. One goes therefore with their synthesis preferably from intermediates of the formula I, which already have this desired configuration on the C-2.

Bei einigen der bekannten Herstellungsverfahren für Verbindungen der Formel I war eine Racematspaltung unverzichtbar, wollte man zu Verbindungen mit einer definierten Konfiguration am C-2 gelangen. In some of the known manufacturing processes for Compounds of formula I was a racemate resolution indispensable if you wanted to connect with one defined configuration on the C-2.  

Aus Tetrahedron Letter 1987 1413-1416 ist ein Verfahren bekannt, mit dessen Hilfe man ausgehend von L-Asparaginsäure in einer insgesamt 12-stufigen Synthese zu optisch einheitlichen Octahydroindol-Derivaten mit einer definierten Konfiguration an C-2 gelangt.A process is known from Tetrahedron Letter 1987 1413-1416 known, with the help of starting from L-aspartic acid in a 12-step synthesis too optical uniform octahydroindole derivatives with a defined configuration at C-2.

Es wurde nun gefunden, daß sich entsprechend substituierte Serinderivate durch Cyclisierung in optisch einheitliche Verbindungen der Formel I mit der gewünschten Konfiguration an C-2 überführen lassen, ohne daß auf irgend einer Stufe dieses neuen Verfahrens eine Racematspaltung notwendig wäre.It has now been found that corresponding substitution takes place Serine derivatives by cyclization in optically uniform Compounds of formula I with the desired configuration transferred to C-2 without being at any stage this new process would require a resolution.

Die Erfindung betrifft ein Verfahren zur Herstellung von Verbindungen der Formel I in welcherThe invention relates to a method for producing Compounds of formula I. in which

n=1, 2 oder 3 R (C₁-C₁₄)-Acyl und R¹ (C₁-C₆)-Alkyl, (C₃-C₇)-Cycloalkyl, (C₇-C₁₁)-Aralkyl oder eine andere Carboxyschutzgruppe bedeuten, n = 1, 2 or 3 are R (C₁-C₁₄) acyl and R¹ (C₁-C₆) alkyl, (C₃-C₇) cycloalkyl, (C₇-C₁₁) aralkyl or another carboxy protecting group,

wobei die Wasserstoffatome an den Brückenkopf-Kohlenstoffatomen 3a und (5+n)a vorzugsweise cis-konfiguriert sind, das dadurch gekennzeichnet ist, daß man Verbindungen der Formel IIwherein the hydrogen atoms on the bridgehead carbon atoms 3a and (5+ n) a are preferably cis-configured, which is characterized in that compounds of the formula II

in welcher n, R und R¹ wie oben definiert sind und Hal Chlor, Brom oder Iod bedeutet, radikalisch cyclisiert.in which n , R and R 1 are as defined above and Hal is chlorine, bromine or iodine, cyclically cyclized.

Wie folgendes Schema zeigt, gelangt man mit Hilfe der erfindungsgemäßen Verfahren ausgehend von beispielsweise 3-Bromcyclopenten (V) und L-Serin (III) in einer insgesamt nur 7-stufigen Synthese zu den optisch einheitlichen Diastereomeren Ia und Ib, die Homologe der oben erwähnten Octahydroindol-Derivate sind. Wenn man das Verfahren über die Stufe des L-Serinbenzylesters durchführt, verringert sich sogar dessen Stufenzahl um eine Stufe auf insgesamt 6 Stufen. As the following diagram shows, the processes according to the invention, starting from, for example, 3-bromocyclopentene (V) and L-serine (III), give the optically uniform diastereomers Ia and Ib, the homologs of the abovementioned ones, in a total of only 7 steps Are octahydroindole derivatives. If the process is carried out via the L-serine benzyl ester stage, the number of stages thereof is even reduced by one stage to a total of 6 stages.

Das Kohlenstoffatom in Position 2 des bicyclischen Ringsystems der Verbindungen der Formeln I und II kann sowohl die R- als auch die S-Konfiguration aufweisen; bevorzugt ist die S-Konfiguration.The carbon atom in position 2 of the bicyclic Ring system of the compounds of the formulas I and II can have both the R and S configurations; the S configuration is preferred.

R ist vorzugsweise (C₁-C₆)-Alkanoyl, (C₆-C₁₀)-Aryl-(C₁-C₄)-alkanoyl, (C₆-C₁₀)-Aroyl, (C₁-C₆)-Alkoxycarbonyl oder (C₇-C₁₁)-Aralkyloxycarbonyl, insbesondere aber (C₁-C₄)-Alkanoyl, wie Acetyl oder Propionyl, Benzoyl oder substituiertes Benzoyl, wie beispielsweise Halogenbenzoyl, Methoxybenzoyl, Dimethoxybenzoyl oder Nitrobenzoyl.R is preferably (C₁-C₆) alkanoyl, (C₆-C₁₀) aryl- (C₁-C₄) alkanoyl, (C₆-C₁₀) aroyl, (C₁-C₆) alkoxycarbonyl or (C₇-C₁₁) aralkyloxycarbonyl, but especially (C₁-C₄) alkanoyl, such as acetyl or Propionyl, benzoyl or substituted benzoyl, such as for example halobenzoyl, methoxybenzoyl, Dimethoxybenzoyl or nitrobenzoyl.

Des weiteren kann R, falls von den vorstehenden Definitionen nicht schon umfaßt, für eine in der Peptidchemie übliche Aminschutzgruppe vom Urethantyp stehen (vgl. z. B. Hubbuch, Kontakte Merck 3/79, 14-22). Schutzgruppen vom Urethantyp sind beispielsweise Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO₂), Z(Hal n ), Dobz, Iboc, Adpoc, Mboc und 1,4-Dimethyl-pyridyl-oxycarbonyl.Furthermore, if not already included in the above definitions, R can represent an amine protecting group of the urethane type which is customary in peptide chemistry (cf., for example, Hubbuch, contacts Merck 3/79, 14-22). Protecting groups of the urethane type are, for example, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z (NO₂), Z (Hal n ), Dobz, Iboc, Adpoc, Mboc and 1,4-dimethyl pyridyl oxycarbonyl.

R¹ ist vorzugsweise (C₁-C₄)-Alkyl, wie z. B. Methyl, Ethyl oder tert.-Butyl, oder (C₇-C₁₁)-Aralkyl, wie beispielsweise Benzyl.R¹ is preferably (C₁-C₄) alkyl, such as. B. methyl, ethyl or tert-butyl, or (C₇-C₁₁) aralkyl, such as Benzyl.

Weiterhin kann R¹, falls von den vorstehenden Definitionen nicht schon umfaßt, für eine in der Peptidchemie übliche Carboxylschutzgruppe stehen (vgl. z. B. oben genannten Artikel von Hubbuch), beispielsweise die schon erwähnte Alkylreste oder Benzyl. Weiter sind modifizierte Benzylreste, wie p-Nitrobenzyl, p-Methoxybenzyl, p-Brombenzyl, p-Chlorbenzyl und Reste wie 4-Picolyl oder Benzoylmethyl geeignet. Furthermore, R1 may, if from the above definitions not already included, for one common in peptide chemistry Carboxyl protecting group (see, e.g., above Hubbuch article), for example the one already mentioned Alkyl radicals or benzyl. There are also modified ones Benzyl radicals, such as p-nitrobenzyl, p-methoxybenzyl, p-bromobenzyl, p-chlorobenzyl and residues such as 4-picolyl or Benzoylmethyl suitable.  

Unter Alkyl wird im vorstehenden und im folgenden geradkettiges oder verzweigtes Alkyl verstanden. Entsprechendes gilt davon abgeleitete Reste wie z. B. Alkanoyl und Aralkyl. Niederalkyl weist vorzugsweise bis zu 6 C-Atome auf. (C₆-C₁₀)-Aryl ist beispielsweise Phenyl oder Naphthyl; bevorzugt ist Phenyl. Entsprechendes gilt für davon abgeleitete Reste wie z. B. Aroyl und Aralkyl.Alkyl is used in the above and in the following straight-chain or branched alkyl understood. The same applies to residues derived from such. B. Alkanoyl and aralkyl. Lower alkyl preferably has up to 6 carbon atoms. (C₆-C₁₀) aryl is, for example, phenyl or Naphthyl; phenyl is preferred. The same applies to residues derived therefrom such as e.g. B. Aroyl and aralkyl.

Die radikalische Cyclisierung kann z. B. mit Trialkylstannanen, wie z. B. mit Tri-n-butylzinnhydrid in einem geeigneten Lösungsmittel zwischen -20°C und 120°C, vorzugsweise zwischen 0°C und dem Siedepunkt des Reaktionsgemisches, insbesondere bei Siedetemperatur gegebenenfalls in Gegenwart eines Radikalinitiators durchgeführt werden. Als Lösungsmittel kommen dabei insbesondere aprotische Lösungsmittel wie Benzol, Toluol oder Xylol in Frage. Geeignete Initiatoren sind beispielsweise organische Peroxide, wie tert.-Butylperoxid, substituierte Azo-alkansäuredinitrile, wie z. B. 2,2′-Azoisobuttersäuredinitril (AIBN), Mercaptane und Stannane; bevorzugt ist AIBN.The radical cyclization can e.g. B. with Trialkylstannanes, such as. B. with tri-n-butyltin hydride in a suitable solvent between -20 ° C and 120 ° C, preferably between 0 ° C and the boiling point of the Reaction mixture, especially at the boiling point optionally in the presence of a radical initiator be performed. Come as a solvent especially aprotic solvents such as benzene, toluene or xylene in question. Suitable initiators are for example organic peroxides, such as tert-butyl peroxide, substituted azo-alkanoic acid dinitriles, such as. B. 2,2'-azoisobutyronitrile (AIBN), mercaptans and Stannane; AIBN is preferred.

Des weiteren kann die radikalische Cyclisierung in einem geeigneten dipolar aprotischen Lösungsmittel zwischen -20°C und dem Siedepunkt des Reaktionsgemisches vorzugsweise zwischen 10 und 50°C durchgeführt werden. Geeignete dipolar aprotische Lösungsmittel sind beispielsweise Ether, wie Diethylether, Tetrahydrofuran und Dioxan.Furthermore, the radical cyclization can be carried out in one suitable dipolar aprotic solvent between -20 ° C and the boiling point of the reaction mixture is preferred between 10 and 50 ° C. Suitable Dipolar aprotic solvents are, for example, ethers, such as diethyl ether, tetrahydrofuran and dioxane.

Man stellt die Verbindungen der Formel II her ausgehend von Cycloalkenylbromiden der Formel XI,The compounds of formula II are prepared starting from Cycloalkenyl bromides of the formula XI,

worin n=1, 2 oder 3 ist. Diese werden mit Serinderivaten der Formel IV, in der R¹ wie oben definiert ist, vorzugsweise (C₁-C₆)-Alkyl oder (C₇-C₁₁)-Aralkyl, wie Methyl oder Benzyl bedeutet und die R- oder S-, vorzugsweise S-konfiguriert sind, in Gegenwart einer Base wie K₂CO₃ in einem dipolar aprotischen Lösungsmittel wie Acetonitril zwischen 0°C und dem Siedepunkt des Reaktionsgemisches, vorzugsweise bei Raumtemperatur zu Verbindungen der Formel XIIwhere n = 1, 2 or 3. These are with serine derivatives of the formula IV, in which R¹ is as defined above, preferably (C₁-C₆) alkyl or (C₇-C₁₁) aralkyl, such as methyl or benzyl, and the R- or S-, preferably S-configured are in the presence of a base such as K₂CO₃ in a dipolar aprotic solvent such as acetonitrile between 0 ° C and the boiling point of the reaction mixture, preferably at room temperature to give compounds of formula XII

worin n und R¹ wie oben definiert sind, umgesetzt.wherein n and R1 are as defined above.

Da die Verbindung der Formel XII als Diastereomerengemisch vorliegen kann, kann dieses gegebenenfalls über Salzbildung und fraktionierte Kristallisation oder durch Chromatographie in die reinen Diastereomeren getrennt werden. Werden die reinen Diastereomeren in die Reaktionsfolge eingesetzt, so entfällt auf einer späteren Stufe die Diastereomerentrennung, was sich dann günstig auf die Gesamtausbeute auswirkt.Since the compound of formula XII as a mixture of diastereomers may be present, this may be via salt formation and fractional crystallization or by Chromatography can be separated into the pure diastereomers. The pure diastereomers in the reaction sequence used, the will not apply at a later stage Diastereomer separation, which then has a favorable effect on the Overall yield affects.

Verbindungen der Formel XII werden nun zu Verbindungen der Formel XIII acyliert,Compounds of the formula XII now become compounds of the Formula XIII acylated,

worin n, R und R¹ wie oben definiert sind. Die Acylierung führt man zweckmäßig vorzugsweise in Gegenwart einer Base in einem dipolar aprotischen Lösungsmittel wie Aceton zwischen -20°C und dem Siedepunkt des Reaktionsgemisches, vorzugsweise bei Raumtemperatur durch. Als Acylierungsmittel kommen beispielsweise die Chloride der Formel RCl oder die Anhydride der Formel R₂O in Frage. Geeignete Basen sind tert. Amine wie Triethylamin und anorganische Basen wie K₂CO₃. wherein n , R and R¹ are as defined above. The acylation is advantageously carried out preferably in the presence of a base in a dipolar aprotic solvent such as acetone between -20 ° C. and the boiling point of the reaction mixture, preferably at room temperature. Examples of suitable acylating agents are the chlorides of the formula RCl or the anhydrides of the formula R₂O. Suitable bases are tert. Amines such as triethylamine and inorganic bases such as K₂CO₃.

Die Umsetzung der Verbindungen der Formel XIII zu Verbindungen der Formel II, worin n, R, R¹ und Hal wie oben definiert sind, erfolgt zweckmäßigerweise so, daß man die Hydroxyfunktion der Verbindungen der Formel XIII durch eine Abgangsgruppe ersetzt. So lassen sich nach bekannten Verfahren beispielsweise die entsprechenden Tosylate, Mesylate oder Triflate herstellen, die anschließend mit Chlorid, Bromid oder Iodid nucleophil in die Verbindungen der Formel II überführt werden können.The conversion of the compounds of the formula XIII to compounds of the formula II, in which n , R, R 1 and Hal are as defined above, is advantageously carried out by replacing the hydroxy function of the compounds of the formula XIII by a leaving group. For example, the corresponding tosylates, mesylates or triflates can be prepared by known processes and can then be converted nucleophilically into the compounds of the formula II using chloride, bromide or iodide.

Chlor kann aber auch direkt eingeführt werden, z. B. durch Umsetzung der Verbindungen der Formel XIII mit PCl₅, Brom z. B. durch Umsetzung mit PBr₃. Die Iodverbindung der Formel II wird zweckmäßigerweise mit Triphenylphosphin und Iod in Gegenwart von Imidazol vorzugsweise bei Raumtemperatur in einem aprotischen unpolaren Lösungsmittel wie z. B. Benzol oder Toluol aus Verbindungen der Formel XIII hergestellt.Chlorine can also be introduced directly, e.g. B. by Implementation of the compounds of formula XIII with PCl₅, bromine e.g. B. by reaction with PBr₃. The iodine compound of the formula II is conveniently in with triphenylphosphine and iodine Presence of imidazole preferably at room temperature in an aprotic non-polar solvent such as. B. Benzene or toluene prepared from compounds of formula XIII.

Die Erfindung betrifft auch die Zwischenprodukte der Formel IIa,The invention also relates to the intermediates of the formula IIa,

in welcherin which

n=1, 2 oder 3, X= Hydroxy, Chlor, Brom oder Iod, R= Wasserstoff oder (C₁-C₁₄)-Acyl und R¹= (C₁-C₆)-Alkyl, (C₃-C₇)-Cycloalkyl, (C₇-C₁₁)-Aralkyl oder eine andere Carboxylschutzgruppe bedeuten. n = 1, 2 or 3, X = hydroxy, chlorine, bromine or iodine, R = hydrogen or (C₁-C₁₄) acyl and R¹ = (C₁-C₆) alkyl, (C₃-C₇) cycloalkyl, (C₇ -C₁₁) aralkyl or another carboxyl protecting group.

Die nachstehenden Beispiele dienen zur Erläuterung der Erfindung, ohne daß diese beschränkt wäre.The following examples serve to explain the Invention without being limited.

Beispiel 1Example 1 N-(2-Cyclopenten-1-yl)-L-serinmethylesterN- (2-Cyclopenten-1-yl) -L-serine methyl ester

Zu 24,5 g L-Serinmethylester-hydrochlorid in 200 ml trockenem Acetonitril werden 48 g festes K₂CO₃ gegeben. Zu dieser Mischung wird 23,2 g Cyclopentenylbromid in Tetrachlorkohlenstoff bei Eiskühlung gegeben. Man läßt auf Raumtemperatur kommen und rührt 2 Stunden bei dieser Temperatur. Nach dem Absaugen des Feststoffes wird das Filtrat eingeengt und der Rückstand über Kieselgel mit CH₂Cl₂ als Elutionsmittel chromatographiert.
Ausbeute: 7,6 g; Fp. 113-126°C
:-30,5° (c=1,13; CH₃OH)48 g of solid K₂CO₃ are added to 24.5 g of L-serine methyl ester hydrochloride in 200 ml of dry acetonitrile. 23.2 g of cyclopentenyl bromide in carbon tetrachloride are added to this mixture while cooling with ice. The mixture is allowed to come to room temperature and stirred at this temperature for 2 hours. After the solid has been filtered off with suction, the filtrate is concentrated and the residue is chromatographed on silica gel using CH₂Cl₂ as the eluent.
Yield: 7.6 g; Mp 113-126 ° C
: -30.5 ° (c = 1.13; CH₃OH)

Beispiel 2Example 2 N-(2-(1S)-Cyclopenten-1-yl)-L-serinmethylesterN- (2- (1S) -cyclopenten-1-yl) -L-serine methyl ester

Das Diastereomerengemisch aus Beispiel 1 wird mit ethanolischer HCl in Essigester in das Hydrochlorid überführt (Fp. 150-160°C, =10,9° (c= 0,96; CH₃OH) und anschließend mehrere Male aus trockenem Acetonitril umkristallisiert. Die S,S-Verbindung (94%ig, als HCl-Salz) hat einen Drehwert von =-67° (c=0,85; CH₃OH); Fp. 180°CThe mixture of diastereomers from Example 1 is converted into the hydrochloride with ethanolic HCl in ethyl acetate (mp. 150-160 ° C, = 10.9 ° (c = 0.96; CH₃OH) and then recrystallized several times from dry acetonitrile. S-compound (94%, as HCl salt) has a rotation value of = -67 ° (c = 0.85; CH₃OH); mp. 180 ° C

Die freie Base wird aus dem Hydrochlorid mit wäßriger K₂CO₃-Lösung freigesetzt.
= -111,7° (c=0,86; CH₃OH)The free base is released from the hydrochloride with an aqueous K₂CO₃ solution.
= -111.7 ° (c = 0.86; CH₃OH)

Beispiel 3Example 3 N-(2-(1R)-Cyclopenten-1-yl)-L-serinmethylesterN- (2- (1R) -cyclopenten-1-yl) -L-serine methyl ester

Analog Beispiel 2 wird die (R,S)-Verbindung als HCl-Salz durch Umkristallisation des Hydrochlorids in trockenen Acetonitril, Essigester und CH₂Cl₂ erhalten (ca. 85%ig).Fp. 152-154°C; =+82,78° (c=0,61; CH₃OH).
der freien Base: +38,3° (c=0,88; CH₃OH)Analogously to Example 2, the (R, S) compound is obtained as an HCl salt by recrystallization of the hydrochloride in dry acetonitrile, ethyl acetate and CH₂Cl₂ (approx. 85%). 152-154 ° C; = + 82.78 ° (c = 0.61; CH₃OH).
the free base: + 38.3 ° (c = 0.88; CH₃OH)

Beispiel 4Example 4 N-Benzyloxycarbonyl-N-(2-(1R,S)-cyclopenten-1-yl)-L-serinmethylester-N-benzyloxycarbonyl-N- (2- (1R, S) -cyclopenten-1-yl) -L-serine methyl ester-

10,5 g Methylester aus Beispiel 1 werden in 164 ml gesättigter wäßriger NaHCO₃-Lösung suspendiert. Dazu wird bei Raumtemperatur 11,24 ml Chlorameisensäurebenzylester gegeben. Nach weiteren 2 Stunden Rühren wird mit Essigester extrahiert. Die organische Phase wird nacheinander mit 2N wäßriger HCl halbgesättigter wäßriger NaHCO₃-Lösung, Wasser und gesättigter wäßriger NaCl-Lösung gewaschen. Nach dem Trocknen wird eingeengt. Der Rückstand wird über Kieselgel mit CH₂Cl₂/Essigester 95 : 5 chromatographiert.Ausbeute: 14,4 g, = -65° (c=1; CH₃OH)10.5 g of methyl ester from Example 1 are suspended in 164 ml of saturated aqueous NaHCO₃ solution. 11.24 ml of benzyl chloroformate are added at room temperature. After stirring for a further 2 hours, the mixture is extracted with ethyl acetate. The organic phase is washed successively with 2N aqueous HCl semi-saturated aqueous NaHCO₃ solution, water and saturated aqueous NaCl solution. After drying, the mixture is concentrated. The residue is chromatographed on silica gel with CH₂Cl₂ / ethyl acetate 95: 5. Yield: 14.4 g, = -65 ° (c = 1; CH₃OH)

Beispiel 5Example 5 2-(S)-(N-Benzyloxycarbonyl-2-(1R,S)-cyclopenten-1-yl-amino)- 3-iod-propionsäuremethylester2- (S) - (N-Benzyloxycarbonyl-2- (1R, S) -cyclopenten-1-yl-amino) - 3-iodo-propionic acid methyl ester

0,412 g Triphenylphosphin und 0,107 g Imidazol werden in 7 ml trockenen Benzol vorgelegt. Dazu werden 0,346 g Iod in 3 ml trockenen Benzol bei Raumtemperatur zugetropft. Es wird nach Ausfallen eines gelben Niederschlages 10 Minuten nachgerührt. Dazu werden bei Raumtemperatur und unter Lichtschutz 0,3 mg des Alkohols aus Beispiel 4 in 2 ml trockenem Benzol zugetropft. Es wird 3 Stunden bei Raumtemperatur gerührt. Danach wird die Mischung auf Ether/Wasser gegossen. Die Etherlösung wird mit Wasser gewaschen, getrocknet und einrotiert. Der Rückstand wird über Kieselgel mit Cyclohexan/Essigester 9 : 1 chromatographiert.
Ausbeute: 0,2 g Öl; Rf: 0,65 (SiO₂; CH₂Cl₂/Essigester 95 : 5; I₂)0.412 g triphenylphosphine and 0.107 g imidazole are placed in 7 ml dry benzene. 0.346 g of iodine in 3 ml of dry benzene are added dropwise at room temperature. After precipitation of a yellow precipitate, stirring is continued for 10 minutes. For this purpose, 0.3 mg of the alcohol from Example 4 in 2 ml of dry benzene are added dropwise at room temperature and with protection from light. It is stirred for 3 hours at room temperature. The mixture is then poured onto ether / water. The ether solution is washed with water, dried and evaporated. The residue is chromatographed on silica gel with cyclohexane / ethyl acetate 9: 1.
Yield: 0.2 g oil; R f : 0.65 (SiO₂; CH₂Cl₂ / ethyl acetate 95: 5; I₂)

Beispiel 6Example 6 N-Benzyloxycarbonyl-(1S,3S,5S)-2-azabicyclo[3,3,0]octan-3- carbonsäuremethylester und N-Benzyloxycarbonyl-(1R,3S,5R)-2- azabicyclo-[3,3,0]-octan-3-carbonsäuremethylesterN-benzyloxycarbonyl- (1S, 3S, 5S) -2-azabicyclo [3,3,0] octane-3- carboxylic acid methyl ester and N-benzyloxycarbonyl- (1R, 3S, 5R) -2- azabicyclo [3,3,0] octane-3-carboxylic acid methyl ester

3,25 g Iodverbindung aus Beispiel 5, 521 mg Azobisisobutyronitril (AIBN) und 2,31 g Tri-n-butylzinnhydrid werden in 260 ml trockenem Benzol gelöst. Es wird 4 Stunden am Rückfluß unter Stickstoff gekocht. Danach wird enrotiert und der Rückstand in Ether aufgenommen. Die Etherlösung wird 30 Minuten mit 10%iger wäßriger KF-Lösung gerührt; nach Filtration wird die Etherlösung getrocknet und einrotiert. Der Rückstand wird über Kieselgel chromatographiert mit Cyclohexan/Essigester 4 : 1.Ausbeute: 2,0 g = -40,5° (c= 1,035; CH₃OH)3.25 g of iodine compound from Example 5, 521 mg of azobisisobutyronitrile (AIBN) and 2.31 g of tri-n-butyltin hydride are dissolved in 260 ml of dry benzene. It is refluxed for 4 hours under nitrogen. The mixture is then rotated and the residue is taken up in ether. The ether solution is stirred for 30 minutes with 10% aqueous KF solution; after filtration, the ether solution is dried and evaporated. The residue is chromatographed on silica gel using cyclohexane / ethyl acetate 4: 1. Yield: 2.0 g = -40.5 ° (c = 1.035; CH₃OH)

Beispiel 7Example 7 N-Benzyloxycarbonyl-(1R,3S,5R)-2-azabicyclo-[3,3,0]-octan-3- carbonsäurebenzylesterN-benzyloxycarbonyl- (1R, 3S, 5R) -2-azabicyclo- [3,3,0] octane-3- carboxylic acid benzyl ester

1 g Diastereomerengemisch aus Beispiel 6 werden in 10 ml Benzylalkohol gelöst, 0,35 ml Titantetraisopropylat zugetropft und in Ölpumpenvakuum 4 Stunden bei 90°C gerührt. Anschließend werden weitere 1,6 ml Titantetraisopropylat zugetropft und 6 Stunden bei 90°C in Ölpumpenvakuum gerührt. Dann wird der Benzylalkohol im Vakuum entfernt und der Rückstand in Ether aufgenommen, der Ether mit 2N wäßriger HCl, dann mit gesättigter wäßriger NaHCO₃-Lösung und nach dem Absaugen des Niederschlages mit gesättigter wäßriger NaCl-Lösung gewaschen. Nach dem Trocknen wird einrotiert. Der Rückstand wird über Kieselgel mit Cyclohexan/Essigester 9 : 1 chromatographiert. Das zuerst eluierte Produkt ist die (1R,3S,5R)-Verbindung (cis, exo-Konfiguration).Ausbeute: 422 mg = 101,6° (c=0,82; CH₃OH)1 g of diastereomer mixture from Example 6 is dissolved in 10 ml of benzyl alcohol, 0.35 ml of titanium tetraisopropylate is added dropwise and the mixture is stirred at 90 ° C. in an oil pump vacuum for 4 hours. A further 1.6 ml of titanium tetraisopropylate are then added dropwise and the mixture is stirred at 90 ° C. in an oil pump vacuum for 6 hours. Then the benzyl alcohol is removed in vacuo and the residue is taken up in ether, the ether is washed with 2N aqueous HCl, then with saturated aqueous NaHCO₃ solution and, after the precipitate has been suctioned off, with saturated aqueous NaCl solution. After drying, it is spun in. The residue is chromatographed on silica gel with cyclohexane / ethyl acetate 9: 1. The first eluted product is the (1R, 3S, 5R) compound (cis, exo configuration). Yield: 422 mg = 101.6 ° (c = 0.82; CH₃OH)

Beispiel 8Example 8 N-Benzyloxycarbonyl-(1S,3S,5S)-2-azabicyclo-[3,3,0]-octan- 3-carbonsäurebenzylesterN-benzyloxycarbonyl- (1S, 3S, 5S) -2-azabicyclo- [3,3,0] octane 3-carboxylic acid benzyl ester

Das nach der cis-exo-Verbindung eluierte Produkt aus Beispiel 7 ist die (1S,3S,5S)-Verbindung (cis, endo-Konfiguration).Ausbeute: 553 mg Öl (aus Ansatz des Beispiels 7) = -2,8° (c=1,1; CH₃OH)The product from Example 7 eluted after the cis-exo compound is the (1S, 3S, 5S) compound (cis, endo configuration). Yield: 553 mg of oil (from the approach of Example 7) = -2.8 ° (c = 1.1; CH₃OH)

Beispiel 9Example 9 (1R,3S,5R)-2-Azabicyclo-[3,3,0]-octan-3-carbonsäure(1R, 3S, 5R) -2-azabicyclo [3,3,0] octane-3-carboxylic acid

400 mg des Endproduktes aus Beispiel 7 werden in 10 ml Ethanol gelöst, dazu 50 mg Pd/C (10%ig) gegeben und 6 Stunden hydriert. Nach Absaugen des Katalysators wird eingeengt und der Rückstand mit Essigester verrührt. Ausbeute: 90 mg; Fp. 220-225°C
= -48,4° (c=0,37; CH₃OH)400 mg of the end product from Example 7 are dissolved in 10 ml of ethanol, 50 mg of Pd / C (10%) are added and the mixture is hydrogenated for 6 hours. After the catalyst has been filtered off with suction, the mixture is concentrated and the residue is stirred with ethyl acetate. Yield: 90 mg; Mp 220-225 ° C
= -48.4 ° (c = 0.37; CH₃OH)

Beispiel 10Example 10 (1S,3S,5S)-2-Azabicyclo-[3,3,0]-octan-3-carbonsäure(1S, 3S, 5S) -2-azabicyclo [3,3,0] octane-3-carboxylic acid

Analog Beispiel 9 werden 500 mg aus Beispiel 8 umgesetzt. Ausbeute: 186 mg; Fp. 235-238°C
= -53° (c= 0,52; CH₃OH)500 mg from Example 8 are reacted analogously to Example 9. Yield: 186 mg; Mp 235-238 ° C
= -53 ° (c = 0.52; CH₃OH)

Claims (7)

1. Verfahren zur Herstellung einer Verbindung der Formel I in welchern=1, 2 oder 3, R (C₁-C₁₄)-Acyl und R¹ (C₁-C₆)-Alkyl, (C₃-C₇)-Cycloalkyl, (C₇-C₁₁)-Aralkyl oder eine andere Carboxylschutzgruppe bedeuten,wobei die Wasserstoffatome an den Brückenkopf-Kohlenstoffatomen 3a und (5+n)a vorzugsweise cis-konfiguriert sind, dadurch gekennzeichnet, daß man eine Verbindung der Formel II in welcher n, R und R¹ wie oben definiert sind und Hal Chlor, Brom oder Iod bedeutet, radikalisch cyclisiert.1. Process for the preparation of a compound of formula I. in which n = 1, 2 or 3, R (C₁-C₁₄) acyl and R¹ (C₁-C₆) alkyl, (C₃-C₇) cycloalkyl, (C₇-C₁₁) aralkyl or another carboxyl protecting group, where the hydrogen atoms on the bridgehead carbon atoms 3a and (5+ n) a are preferably cis-configured, characterized in that a compound of the formula II in which n , R and R 1 are as defined above and Hal is chlorine, bromine or iodine, cyclically cyclized. 2. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß man eine Verbindung der Formel II cyclisiert, in welcher R (C₁-C₆)-Alkanoyl, (C₆-C₁₀)-Aryl-(C₁-C₄)-alkanoyl, (C₆-C₁₀)-Aroyl, (C₁-C₆)-Alkoxycarbonyl oder (C₇-C₁₁)-Aralkyloxycarbonyl bedeutet.2. The method according to claim 1, characterized in that one cyclizes a compound of formula II in which R (C₁-C₆) alkanoyl, (C₆-C₁₀) aryl- (C₁-C₄) alkanoyl, (C₆-C₁₀) aroyl, (C₁-C₆) alkoxycarbonyl or (C₇-C₁₁) aralkyloxycarbonyl means. 3. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß man eine Verbindung der Formel II cyclisiert, in welcher R für eine in der Peptidchemie übliche Aminschutzgruppe vom Urethantyp steht. 3. The method according to claim 1, characterized in that one cyclizes a compound of formula II in which R for an amine protecting group customary in peptide chemistry of the urethane type.   4. Verfahren gemäß einem oder mehreren der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß man eine Verbindung der Formel II cyclisiert, in welcher R¹ (C₁-C₄)-Alkyl oder (C₇-C₁₁)-Aralkyl bedeutet.4. The method according to one or more of claims 1 to 3, characterized in that a connection of the Formula II cyclized in which R¹ (C₁-C₄) alkyl or (C₇-C₁₁) aralkyl means. 5. Verfahren gemäß einem oder mehreren der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß man eine Verbindung der Formel II cyclisiert, in welcher R¹ für eine in der Peptidchemie übliche Carboxylschutzgruppe steht.5. The method according to one or more of claims 1 to 3, characterized in that a connection of the Formula II cyclized, in which R¹ for one in the Peptide chemistry usual carboxyl protecting group. 6. Verbindung der Formel IIa, in welchern= 1, 2 oder 3, X= Hydroxy, Chlor, Brom oder Iod, R= Wasserstoff oder (C₁-C₁₄)-Acyl und R¹= (C₁-C₆)-Alkyl, (C₃-C₇)-Cycloalkyl, (C₇-C₁₁)-Aralkyl oder eine andere Carboxylschutzgruppe bedeuten.6. compound of the formula IIa, in which n = 1, 2 or 3, X = hydroxy, chlorine, bromine or iodine, R = hydrogen or (C₁-C₁₄) acyl and R¹ = (C₁-C₆) alkyl, (C₃-C₇) cycloalkyl, (C₇-C₁₁) aralkyl or another carboxyl protecting group. 7. Verwendung einer Verbindung der Formel IIa gemäß Anspruch 6 bei der Synthese eines ACE-Inhibitors.7. Use of a compound of formula IIa according to Claim 6 in the synthesis of an ACE inhibitor.
DE19873722007 1987-07-03 1987-07-03 METHOD FOR PRODUCING BICYCLIC AMINOCARBONIC ACIDS, INTERMEDIATE PRODUCTS OF THIS METHOD AND THE USE THEREOF Withdrawn DE3722007A1 (en)

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FI883141A FI92691C (en) 1987-07-03 1988-06-30 Process for the preparation of bicyclic amino carboxylic acids and intermediates used in this process
CA000572358A CA1332422C (en) 1987-07-03 1988-06-30 Process for the preparation of bicyclic amino carboxylic acids, intermediates in this process, and their use
HU883459A HU203533B (en) 1987-07-03 1988-07-01 Process for producing bicyclic amino-carboxylic acids
JP63162750A JP2564614B2 (en) 1987-07-03 1988-07-01 Method for producing bicyclic aminocarboxylic acid
IE201988A IE66150B1 (en) 1987-07-03 1988-07-01 A process for the preparation of bicyclic amino carboxylic acids intermediates in this process and their use
US07/214,457 US5011940A (en) 1987-07-03 1988-07-01 Process for the preparation of bicyclic amino carboxylic acids, intermediates in this process, and their use
NO882957A NO173864C (en) 1987-07-03 1988-07-01 Process for Preparation of Bicyclic Aminocarboxylic Acids, and Intermediate of the Process
KR1019880008172A KR960012363B1 (en) 1987-07-03 1988-07-01 Process for the preparation of bicyclic aminocarboxylic acids
ZA884727A ZA884727B (en) 1987-07-03 1988-07-01 A process for the preparation of bicyclic amino carboxylic acids,intermediates in this process,and their use
DK367488A DK170373B1 (en) 1987-07-03 1988-07-01 Process for preparing condensed proline derivatives, as well as intermediates in this process
AU18602/88A AU617328B2 (en) 1987-07-03 1988-07-01 A process for the preparation of bicyclic amino carboxylic acids, intermediates in this process, and their use
NZ225253A NZ225253A (en) 1987-07-03 1988-07-01 Preparation of bicyclic amino carboxylic acid derivatives and intermediates therefor
PT87904A PT87904B (en) 1987-07-03 1988-07-01 PROCESS FOR THE PREPARATION OF BICYCLIC ACID AND BODY PRODUCTS FOR THEIR PREPARATION
IL86943A IL86943A0 (en) 1987-07-03 1988-07-01 Process for the preparation of bicyclic amino carboxylic acids and novel compounds obtained by such process
ES88110612T ES2065899T3 (en) 1987-07-03 1988-07-02 PROCEDURE FOR THE PREPARATION OF BICYCLE AMINO CARBOXYL ACIDS, INTERMEDIATE PRODUCTS OF THIS PROCEDURE AND THEIR USE.
EP88110612A EP0297620B1 (en) 1987-07-03 1988-07-02 Process for the preparation of byciclic aminocarboxylic acids, intermediates for this process and their use
AT88110612T ATE114642T1 (en) 1987-07-03 1988-07-02 PROCESS FOR THE PREPARATION OF BICYCLIC AMINOCARBONIC ACIDS, INTERMEDIATE PRODUCTS OF THAT PROCESS AND THEIR USE.
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FI883141A (en) 1989-01-04
HU203533B (en) 1991-08-28
JP2564614B2 (en) 1996-12-18
ATE114642T1 (en) 1994-12-15
AU1860288A (en) 1989-01-05
CA1332422C (en) 1994-10-11
FI92691B (en) 1994-09-15
AU617328B2 (en) 1991-11-28
FI883141A0 (en) 1988-06-30
FI92691C (en) 1994-12-27
KR960012363B1 (en) 1996-09-20
HUT50120A (en) 1989-12-28
EP0297620A3 (en) 1991-06-05
IL86943A0 (en) 1988-12-30
DK367488A (en) 1989-01-04
NZ225253A (en) 1990-12-21
NO882957L (en) 1989-01-04
KR890001984A (en) 1989-04-07
ZA884727B (en) 1989-03-29
PT87904A (en) 1989-06-30
IE882019L (en) 1989-01-03
US5011940A (en) 1991-04-30
EP0297620A2 (en) 1989-01-04
NO882957D0 (en) 1988-07-01
ES2065899T3 (en) 1995-03-01
DK170373B1 (en) 1995-08-14
IE66150B1 (en) 1995-12-13
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PT87904B (en) 1995-03-01
JPS6434960A (en) 1989-02-06

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